Cosmetic use of botulinum toxin for the treatment of eyebrow and forehead ptosis, and unwanted eyebrow expression

ABSTRACT

A method of temporarily elevating the eyebrow position and softening undesirable glabellar muscle activity to affect a more desirable appearance. In a broad aspect the invention comprises injecting small quantities of botulinum toxin (BTX) dissolved in microdroplets of injectable saline carrier to treat the septal and orbital orbicularis oculi muscles, on each side of a patient&#39;s face. In sufficient numbers, injected microdroplets of BTX are able to selectively weaken these muscles. This method preferably also includes using microdroplets of BTX to treat: a) the depressor supercilii muscle, on each side; b) the procerus muscle; c) the corrugator supercilii muscle, on each side; and d) the inferior limit of the frontalis muscle where it meets the superior aspect of the orbital portion of the orbicularis oculi muscle.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. Ser. No. 11/429,057 entitled “CosmeticUse of Botulinum Toxin for the Treatment of Eyebrow and Forehead Ptosis,and Unwanted Eyebrow Expression”, filed May 4, 2006. The content of U.S.Ser. No. 11/429,057 is incorporated by reference herein in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to the cosmetic use ofneurotoxin agents and more particularly to an improved method forinjecting botulinum toxin (BTX).

2. Description of the Related Art

The position and appearance of the eyebrows is determined at rest anddynamically by the opposing action of several groups of muscles that acton the eyebrow. The frontalis muscle primarily performs eyebrowelevation. Brow elevation is opposed by the septal and orbital portionsof the orbicularis oculi muscle, including the depressor superciliicomponent of the orbicularis oculi muscle, and the procerus muscle (D.Knize (1996) An anatomically based study of the mechanisms of eyebrowptosis; Plast. Reconstr. Surg. 97:1321-33). The medial position of theeyebrow is also determined by the activity of the corragator superciliimuscle. Additionally the shape of the brows is also determined by theactivities of the eyebrow elevators and the eyebrow depressor muscleswhere they interdigitate along the eyebrow to create facial expression(A. Karacalar, et al (2005) Compensatory brow asymmetry: anatomic studyand clinical experience; Aesthetic Plast. Surg 29: 119-23).

An aesthetically pleasing appearance is associated with relatively fewlines in the forehead, no creasing between the eyebrows at the root ofthe nose, commonly known as the worry line, no lines across the bridgeof the nose, and an absence of facial lines lateral to the eyes,commonly known as crow's feet. Additionally, with age there is a gradualfall in the position of the eyebrows creating hooding over the uppereyelids, which is known as brow ptosis. Aesthetically this change makesthe eyes look small and is not desirable. Hooding of the upper eyelidsby the descending eyebrow tissue results in a neural reflex thatincreases the activity of the frontalis muscle in an effort to keep thevision clear of the descending tissue that would otherwise obstructvision or interfere with eyelid function (S. Teske, et. al. (1998)Hering's law and eyebrow position; Ophthal. Plast. Reconstr. Surg. 14:105-6).

Botulinum toxin (BTX), which is produced by the bacterium Clostridiumbotulinum, inhibits the release of acetylcholine at the neuromuscularjunction weakening muscle contraction. The degree of muscle paralysiswill vary with the intensity of neuromusclular blockade. Severalimmunologically distinct botulinum toxin serotypes have been identifiedincluding A, B, C, D, E, F, and G. They vary in the severity andduration of the neuromuscular blockade and, consequently, the severityof the paralysis they produce (J. Melling, et. al. (1988) Clostridiumbotulinum toxins: nature and preparation for clinical use; Eye 2:16-23). The term BTX is the generic term for this family of neurotoxins.Botulinum toxin A (BTX-A) is currently available from two commercialsources: Allergan Inc., Irvine, Calif., under the trade name BOTOX®, andfrom Ipsen Ltd., Slough, UK under the trade names Dysport® and Reloxin®.Botulinum toxin B (BTX-B) is available from Solstice Neurosciences, Inc,South San Francisco, Calif., under the trade name Myobloc®. The relativestrengths of these products vary. For purposes of clarity, dose anddilutions in the following discussions will refer to the widelyavailable botulinum toxin A product by Allergan Inc. (BOTOX®). The doseand dilution must be adjusted for the other commercially availablebotulinum products according to their relative strength.

The first clinical application of botulinum toxin was by Dr. Allan Scottfor the treatment of strabismus and then for a form of localized eyeliddystonia known as blepharospasm (A. Scott, et. al. (1973) Pharmacologicweakening of extraocular muscles; Invest Ophthalmol. 12:924-7). Thesewere the first clinical applications approved by the FDA for treatmentwith botulinum toxin A (P. Savino and M. Maus (1991) Botulinum toxintherapy; Neurol. Clin. 9:205-24). Clinical use of botulinum toxin A inthe treatment of spastic facial disorders lead to the clinicalobservation that many of the treated patients had improvement in thedeep glabellar furrows between the eyebrows (J. Carruthers and A.Carruthers (1992) Treatment of glabellar frown lines with C. botulinum-Aexotoxin; J. Dermatol. Surg. Oncol. 18:17-21). Recently, FDA approvalwas granted for the cosmetic use of botulinum toxin A for the treatmentof the worry line between the eyebrows. Other FDA indications forbotulinum toxin A include treatment for cervical dystonia, a type ofneck spasm, and axillary hyperhydrosis, also known as excessive armpitsweating (R. Bhidayasiri and D. Truong (2005) Expanding use of botulinumtoxin; J. Neurol. Sci. 235:1-9).

Botulinum toxin A is clinically used more broadly than what is approvedby the FDA. This wider usage is permissible for licensed physicians andis referred to as “off label” use (J. Carruthers and A. Carruthers(2004) Botox: beyond wrinkles; Clin. Dermatol. 22:89-93). Cosmetically,BTX is used to soften dimpling in the chin, relax the depressor angulioris muscle that contributes to a turned down corners of the mouth asdetailed by Carruthers in U.S. Pat. No. 6,358,917, and a range oflocations and effects around the eyes and in the forehead. Previously,BTX has been used to elevate the eyebrow position by treating betweenthe eyebrows and at the lateral eyebrow with relatively few injectionsites (2-4) and with relatively large quantities of BTX (1.5-2.5 UnitsBotulinum toxin A) (W. Huang, et. al. (2000) Browlift with botulinumtoxin; Dermatol. Surg. 26:55-60). This technique is limited by fear ofinducing the undesired side effect of ptosis of the upper eyelid, wherethe upper eyelid droops causing visual obstruction. This can be causedby the unwanted diffusion of BTX into the eyelid affecting the levatorpalpebrae superioris muscle responsible for eyelid elevation (A.Trindade De Alemeida and S. Cernea (2001) Regarding browlift withbotulinum toxin; Dermatol. Surg. 27:848-849).

As will be disclosed below, the present inventor has found that it ispossible to treat the eyebrow depressors extensively yet avoid theunwanted side effects by using a microdroplet injection technique andtrapping the injected BTX between the skin and the orbicularis oculimuscle, the most important eyebrow depressor.

SUMMARY OF THE INVENTION

The present invention is a method of temporarily elevating the eyebrowposition and softening undesirable glabellar muscle activity to affect amore desirable appearance. In a broad aspect the invention comprisesinjecting small quantities of botulinum toxin (BTX) dissolved inmicrodroplets of injectable saline carrier to treat the septal andorbital orbicularis oculi muscles, on each side of a patient's face. Insufficient numbers, injected microdroplets of BTX are able toselectively weaken these muscles. This method preferably also includesusing microdroplets of BTX to treat: a) the depressor supercilii muscle,on each side; b) the procerus muscle; c) the corrugator superciliimuscle, on each side; and d) the inferior limit of the frontalis musclewhere it meets the superior aspect of the orbital portion of theorbicularis oculi muscle. As the term is used herein, a microdroplet isdefined as 0.01 to 0.05 milliliters of injectable saline, which is usedas an injectable carrier for a dissolved quantity of BTX, creating a BTXsolution. The quantity of BTX dissolved in a microdroplet will vary withthe BTX product chosen and the clinical effect desired. BTX is highlypotent so that even with the highest doses of BTX used clinically, thesolution comprising the microdroplet will be mostly water by weight andvolume. While the quantity of BTX in a microdroplet may vary from 0.001to 1.0 Units of botulinum toxin A (BOTOX®, Allergan Inc.), in thepreferred embodiment, a microdroplet will typically contain 0.25 to 0.5Units of botulinum toxin A. As noted above, microdroplets of otherbotulinum toxin products must be adjusted by the number of Units basedon their relative strength.

The microdroplet injections are preferably placed approximately 0.5 to 1millimeter below the skin surface to distribute the BTX between the skinand the underlying muscle to limit the diffusion of the BTX.

The present method alleviates or improves eyebrow ptosis. This methodmakes use of the fact that the orbital orbicularis oculi muscle insertsinto the skin and therefore resides just below the dermis layer of theskin. Small quantities of BTX placed superficially by needle between thedermis and the orbicularis oculi muscle will tend to be trapped at thesite of placement causing a more localized effect than larger quantitiesof BTX injected deep to the orbicularis oculi muscle. Limiting thevolume and quantity of BTX injected into each site further reduces therisk of BTX diffusion.

As noted above, the microdroplet injection volume at each site is in arange between 0.01 to 0.05 ml. Each microdroplet of BTX injectedcontains 0.001 to 1.0 Units of botulinum toxin A adjusted based on thedesired degree of muscle weakening. In the current preferred embodiment,the BTX solution is prepared so that each microdroplet contains 0.25 to0.5 Units of botulunum toxin A. Typical total dosages of BTX-Aadministered during a treatment vary between 25-75 Units adjusted basedon the muscle mass of the individual being treated and the desireddegree of muscle weakening. The cumulative effect of these microdropletinjections of BTX is selective weakening of the eyebrow depressor effectof the orbicularis oculi muscle, including the depressor supercilliportion of this muscle. The microdroplet treatment also preferablyincludes the procerous muscle and the corragator muscle to weaken all ofthe muscles at the orbital rim that contribute to eyebrow depression.

The method of BTX administration of the present invention makes itpossible to extensively treat the area below the eyebrow withoutunwanted side effects. Previous treatments methods avoided this areabecause they commonly produced a fall in the position of the eyelid withvisual obstruction known as upper eyelid ptosis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of the facial muscles showing the location ofthe muscles to be injected in accordance with the principles of thepresent invention.

FIG. 2 illustrates a typical periocular microdroplet BTX treatment, inaccordance with the principles of the present invention, in which eachindividually injected microdroplet is depicted with a circle.

FIG. 3 is an illustration of the cross-section of the orbit that showsthe relationship of the levator palbepra superioris muscle to theorbicularis oculi muscle.

DETAILED DESCRIPTION OF THE INVENTION

Botulinum toxin is a general term for any of the neurotoxins produced byany of the members the bacterial organisms that belong to theClostridium botulinum species. Fourteen pathogenic strains of thisspecies have been isolated from botulism outbreaks in humans andanimals. These organisms have been shown to produce sevenimmunologically distinct types of neurotoxin (types A, B, C, D, E, F,and G). The term “BTX” is used to refer to this family of neurotoxins.Currently only botulinum toxin types A and B are commercially availablefor clinical use: Botulinum toxin A from Allergan Inc., Irvine, Calif.,under the trade name BOTOX®, and from Ipsen Ltd., Slough, UK, under thetrade name Dysport® and Reloxin®. Botulinum toxin B is available fromSolstice Neurosciences, Inc, South San Francisco, Calif., under thetrade name Myobloc®.

The treatment dose of BTX is measured in “Unit” equivalents, which isdefined on the basis of a biological assay. One Unit equivalent isdefined as the mean LD₅₀ (the dose that is lethal for 50% of the animalstested) for female Swiss Webster mice with a weight of 18-20 grams(Schantz E J, Kaultner D A (1978) Standardized assay for Clostridiumbotulinum toxins. J Assoc Anal Chem 61:96-99. The estimated LD₅₀ forBOTOX® (botulinum toxin A) for a 70 kg adult human is 2800 Units (40Units/kg). Dysport® is roughly ten times less potent than the BOTOX®product. The Botulinum toxin B product Myobloc® is 30 to 50 times lesspotent than the BOTOX® product. Consequently, the dose of these agentsmust be adjusted to achieve an equivalent treatment effect.

Commercially available BTX-A comes in a unit dose form that isreconstituted just prior to use. Currently the only BTX-A approved bythe FDA is BOTOX® from Allergan Inc. This product is packaged in a 100Unit vial as a sterile lyophilized powder stored at 8 degrees C. or lessuntil use. The toxin is dissolved with unpreserved normal saline (sodiumchloride 0.9% for injection) just prior to use to form a solution of agiven dilution based on the volume of saline used to reconstitute theBTX-A. The manufacturer recommends that it be used within 4 hours afterreconstitution to avoid loss of potency. The saline is introduced afterbreaking the vacuum present in the unit vial to avoid foaming of thesolution, which may affect the potency.

The vial that the commercially available BTX products come in have arubber stopper which permits the reconstituted solution to be drawn upwithout removing the rubber stopper that seals the vial. This stopper iscleaned with an alcohol wipe and allowed to dry. An 18-gauge needle on atuberculin type syringe is used to draw up the desired volume ofsolution. In the case of BOTOX®, the concentration of the solution isdetermined by the quantity of saline used to reconstitute the BTX-A inthe vial. For this method, typically 2 to 4 ml of unpreserved saline areused to reconstitute the lyophilized product. These volumes of dilutionproduce concentrations that vary from 25 Units to 50 Units permilliliter or 2.5 Units to 5 Units per 0.1 milliliter or 0.25 to 0.5Units per 0.01 milliliter. Prior to treatment the 18-gauge needle isremoved and replaced with a 30, 31 or 32 gauge needle with 8 to 13 mmlength. The presently available BTX-B product comes as a solutioncontaining 5000 Units per milliliter and can be diluted as needed.

Referring now to FIG. 1, an illustration of the facial muscles is shown,illustrating the location of the muscles to be injected and othersurrounding muscles. The muscles to be injected include portions of theorbicularis oculi muscle, designated generally as 1, including theorbital portion 1 a and the septal portion 1 b. The tarsal portion 1 cis generally avoided to prevent weakness of lid closure. Other musclespreferably injected include the depressor supercilli muscle 2, theprocerous muscle 3, the frontalis muscle 4, the corragator supercillimuscle 5, and d) the inferior limit of the frontalis muscle where itmeets the superior aspect of the orbital portion 1 a of the orbicularisoculi muscle (as shown by numeral designation 6). Treatment of thefrontalis muscle is strictly limited to the inferior portion on eachside that interdigitates with the opposing orbital portion of theorbicularis oculi muscle. Interaction of these two muscle groups at thislocation is responsible for muscular pinching along the eyebrow, whichis generally undesirable.

Patients are typically seated upright in a chair with a headrest toprevent movement. The skin is typically lightly anesthetized with atopical anesthetic or with ice. Next the skin is cleaned with alcoholand allowed to dry. A tuberculin syringe holds 1 milliliter of solution.The needle is inserted just below the dermis, which along the eyebrow isone millimeter below the skin surface. The goal is to place themedication between the skin and the muscle to be treated. A microdropletof BTX is injected at each site. Each microdroplet contains 0.001 to 1.0Units of botulinum toxin A (BOTOX®, Allergan Inc.) in 0.01 to 0.05milliliters of injectable saline. In the preferred embodiment of theinvention, the typical microdroplet will contain 0.25 to 0.5 Units ofBTX-A. Very little diffusion of the BTX occurs when the medication isplaced in this fashion.

FIG. 2 demonstrates a typical treatment pattern, with each individuallyinjected micro-droplet depicted with a circle (circles being designatedby numeral designations 7). Patients are advised not to massage the areaor work out for 24 hours to further reduce the likelihood of dissipationof the toxin. The total dose of BTX-A may vary from 10 Units to 100Units depending on the individual treatment plan. Most patients benefitfrom doses in the range of 30 to 60 Units. A total treatment may requirebetween 30 and 100 treatment sites.

In contrast, prior described applications of BTX along the brow havemade no attempt to keep the agent placed between the skin and the muscleand rely on larger aliquots of medication. (A. Chen and A. Frankel(2003) Altering brow contour with botulinum toxin; Facial Plast. Surg.Clin. North Am. 11: 457-64). Consequently, the injected BTX can diffusecreating unwanted side effects. In particular, injections below theeyebrow have been avoided because the risk of diffusion of the agentinto the eyelid causing unwanted weakening of the levator palebebraesuperioris, the muscle that raises the eyelid, producing an unwanteddroop of the eyelid (S. Huilgol, A. Carruthers, and J. Carruthers (1999)Raising eyebrows with botulinum toxin; Dermatol. Surg. 1999: 373-5).

Referring to FIG. 3, the close proximity of the levator palebebraesuperioris muscle 8 and its tendon 9 to the orbital 1 a, septal 1 b, andtarsal 1 c portions of the orbicularis oculi muscle 1 can beappreciated. By placing low volume microdroplets of BTX with as littleas 0.01 milliliters of volume just below the dermis, unwanted diffusionand side effects are avoided. This permits treatment of larger areas ofthe orbicularis oculi muscle in the upper eyelid and below the eyebrowwhich results in an elevation of the eyebrow tissue in a manner that isnot possible with previously described techniques that specificallyavoid treating this area. It is the use of microdroplets of BTX solutionplaced just below the skin surface that makes the treatment of this areapossible. By weakening a much larger percentage of the orbicularis oculimuscle, the muscle primarily responsible for eyebrow depression, in theupper eyelid above the eyelid crease, in the sub-eyebrow area, at andjust above the eyebrow, laterally in the crows feet area and along themedial aspect of the nose in this controlled manner, a profound foreheadlift is possible. This degree of lift is not achievable with previouslydescribed methods without the risk of affecting the levator palebebraesuperioris muscle deep in the eyelid that is responsible for elevatingthe upper eyelid. When diffusion of BTX deep into the eyelid occurs,partial or complete paralysis of the upper eyelid can occur preventingthe opening of the eyelid. This undesired effect while temporary isunacceptable to those being treated.

The microdroplet method can also be used to treat the depressorsupercilli, procerus muscle and the corrugators, which also contributeto brow depression in the center of the brow region over the root of thenose.

Other embodiments and configurations may be devised without departingfrom the spirit of the invention and the scope of the appended claims.

1. A method of temporarily elevating the eyebrow position and softening undesirable glabellar muscle activity to effect a more desirable appearance, comprising: injecting small quantities of botulinum toxin (BTX) dissolved in microdroplets of injectable saline carrier to treat the septal and orbital orbicularis oculi muscles, on each side of a patient's face, said microdroplets in large enough numbers being sufficient to selectively weaken these muscles.
 2. The method of claim 1, further including the step of injecting small quantities of BTX dissolved in microdroplets to treat the depressor supercilii muscle, on each side.
 3. The method of claim 1, further including the step of injecting small quantities of BTX dissolved in microdroplets to treat the procerus muscle.
 4. The method of claim 1, further including the step of injecting small quantities of BTX dissolved in microdroplets to treat the corrugator supercilii muscle, on each side.
 5. The method of claim 1, further including the step of injecting small quantities of BTX dissolved in microdroplets to treat the inferior limit of the frontalis muscle where it meets the superior aspect of the orbital portion of the orbicularis oculi muscle.
 6. The method of claim 1, further including the steps of injecting small quantities of BTX dissolved in microdroplets to treat: a) the depressor supercilii muscle, on each side; b) the procerus muscle; c) the corrugator supercilii muscle, on each side; and d) the inferior limit of the frontalis muscle where it meets the superior aspect of the orbital portion of the orbicularis oculi muscle.
 7. The method of claim 1, wherein said microdroplet injections are placed 0.5 to 1 millimeter below the skin surface to distribute the BTX between the skin and the underlying muscles to limit the diffusion of the BTX.
 8. The method of claim 1, wherein the BTX is locally administered using microdroplet volumes of BTX solution in amounts between about 0.01 milliliters and 0.05 milliliters.
 9. The method of claim 1, wherein the botulinum toxin (BTX) is selected from the group consisting of botulinum toxin types A, B, C, D, E, F, and G as produced by the Clostridium botulinum bacterium.
 10. The method of claim 1, wherein the BTX is botulinum toxin A (BTX-A).
 11. The method of claim 1, wherein each microdroplet injected contains 0.001 to 1.0 Units of Botulinum toxin A adjusted based on the desired degree of muscle weakening.
 12. The method of claim 1, wherein the concentration of the BTX solution prepared for microdroplet administration is adjusted based on the relative strength of the BTX product used and the desired degree of muscle weakening.
 13. The method of claim 1, wherein each microdroplet contains 0.25 to 0.5 Units of BTX-A.
 14. The method of claim 1, wherein 30 to 90 microdroplet injections are distributed over the muscle groups to be treated.
 15. The method of claim 1, wherein the distribution of the microdroplet injections are adjusted to enhance brow shape and symmetry. 